US7220569B2 - Nucleic acids encoding factor X analogues having a modified protease cleavage site - Google Patents
Nucleic acids encoding factor X analogues having a modified protease cleavage site Download PDFInfo
- Publication number
- US7220569B2 US7220569B2 US10/407,123 US40712303A US7220569B2 US 7220569 B2 US7220569 B2 US 7220569B2 US 40712303 A US40712303 A US 40712303A US 7220569 B2 US7220569 B2 US 7220569B2
- Authority
- US
- United States
- Prior art keywords
- factor
- analogue
- nucleic acid
- recombinant nucleic
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime, expires
Links
- 108010014173 Factor X Proteins 0.000 title claims abstract description 283
- 108091005804 Peptidases Proteins 0.000 title claims abstract description 109
- 239000004365 Protease Substances 0.000 title claims abstract description 108
- 108020004707 nucleic acids Proteins 0.000 title claims abstract description 37
- 102000039446 nucleic acids Human genes 0.000 title claims abstract description 37
- 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 37
- 238000003776 cleavage reaction Methods 0.000 title abstract description 78
- 230000007017 scission Effects 0.000 title abstract description 78
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 title abstract 2
- 108010074860 Factor Xa Proteins 0.000 claims abstract description 132
- 238000012545 processing Methods 0.000 claims abstract description 65
- 230000004913 activation Effects 0.000 claims abstract description 58
- 238000012986 modification Methods 0.000 claims abstract description 48
- 230000004048 modification Effects 0.000 claims abstract description 48
- 102000035195 Peptidases Human genes 0.000 claims description 107
- 108090001126 Furin Proteins 0.000 claims description 97
- 210000004027 cell Anatomy 0.000 claims description 54
- 150000001413 amino acids Chemical class 0.000 claims description 52
- 238000000338 in vitro Methods 0.000 claims description 33
- 102100035233 Furin Human genes 0.000 claims description 27
- 102000012479 Serine Proteases Human genes 0.000 claims description 24
- 108010022999 Serine Proteases Proteins 0.000 claims description 24
- 101710118538 Protease Proteins 0.000 claims description 22
- 108010080805 Factor XIa Proteins 0.000 claims description 16
- 108010071241 Factor XIIa Proteins 0.000 claims description 15
- 108060005987 Kallikrein Proteins 0.000 claims description 15
- 102000001399 Kallikrein Human genes 0.000 claims description 15
- 238000001727 in vivo Methods 0.000 claims description 13
- 108010029144 Factor IIa Proteins 0.000 claims description 11
- 101710172072 Kexin Proteins 0.000 claims description 11
- 210000004899 c-terminal region Anatomy 0.000 claims description 8
- 230000037430 deletion Effects 0.000 claims description 6
- 238000012217 deletion Methods 0.000 claims description 6
- 239000013598 vector Substances 0.000 claims description 6
- 230000035772 mutation Effects 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 230000037431 insertion Effects 0.000 claims description 4
- 238000003780 insertion Methods 0.000 claims description 4
- 241000024188 Andala Species 0.000 claims description 2
- 229940012426 factor x Drugs 0.000 description 261
- 235000019419 proteases Nutrition 0.000 description 81
- 238000002360 preparation method Methods 0.000 description 75
- 102000004961 Furin Human genes 0.000 description 70
- 230000000694 effects Effects 0.000 description 44
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 42
- 108091034117 Oligonucleotide Proteins 0.000 description 41
- 230000014509 gene expression Effects 0.000 description 31
- 238000000034 method Methods 0.000 description 29
- 238000004113 cell culture Methods 0.000 description 27
- 239000012634 fragment Substances 0.000 description 26
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 25
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 25
- 238000003752 polymerase chain reaction Methods 0.000 description 24
- 238000011534 incubation Methods 0.000 description 22
- 108090000623 proteins and genes Proteins 0.000 description 22
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 21
- 108090000765 processed proteins & peptides Proteins 0.000 description 21
- 230000002950 deficient Effects 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 230000008569 process Effects 0.000 description 19
- 101800001401 Activation peptide Proteins 0.000 description 18
- 102400000069 Activation peptide Human genes 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 239000012228 culture supernatant Substances 0.000 description 17
- 102000004196 processed proteins & peptides Human genes 0.000 description 17
- 239000006228 supernatant Substances 0.000 description 17
- 101100275473 Caenorhabditis elegans ctc-3 gene Proteins 0.000 description 16
- 125000003275 alpha amino acid group Chemical group 0.000 description 16
- 229920001184 polypeptide Polymers 0.000 description 16
- 238000001262 western blot Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 239000002243 precursor Substances 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- 108010054218 Factor VIII Proteins 0.000 description 12
- 102000001690 Factor VIII Human genes 0.000 description 12
- 229960000301 factor viii Drugs 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- 108020004414 DNA Proteins 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000013613 expression plasmid Substances 0.000 description 8
- 239000013604 expression vector Substances 0.000 description 8
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- 230000023555 blood coagulation Effects 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 108010054265 Factor VIIa Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 208000009292 Hemophilia A Diseases 0.000 description 6
- 108010018823 anti-inhibitor coagulant complex Proteins 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000015271 coagulation Effects 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 6
- 238000010276 construction Methods 0.000 description 6
- 229940012414 factor viia Drugs 0.000 description 6
- 229940105776 factor viii inhibitor bypassing activity Drugs 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- 102100022641 Coagulation factor IX Human genes 0.000 description 5
- 101001030665 Dictyostelium discoideum GDP-L-fucose synthase Proteins 0.000 description 5
- 108010062466 Enzyme Precursors Proteins 0.000 description 5
- 102000010911 Enzyme Precursors Human genes 0.000 description 5
- 108010076282 Factor IX Proteins 0.000 description 5
- 208000031220 Hemophilia Diseases 0.000 description 5
- 108020004511 Recombinant DNA Proteins 0.000 description 5
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 5
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 230000000468 autoproteolytic effect Effects 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 108090001015 cancer procoagulant Proteins 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 229960004222 factor ix Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 108010014806 prothrombinase complex Proteins 0.000 description 5
- 238000003259 recombinant expression Methods 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- 102100023804 Coagulation factor VII Human genes 0.000 description 4
- 108020004705 Codon Proteins 0.000 description 4
- 108010023321 Factor VII Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 108020005038 Terminator Codon Proteins 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 208000015294 blood coagulation disease Diseases 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- -1 except RVV Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229940012413 factor vii Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010048049 Factor IXa Proteins 0.000 description 3
- 101100170937 Mus musculus Dnmt1 gene Proteins 0.000 description 3
- 108010094028 Prothrombin Proteins 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 239000006143 cell culture medium Substances 0.000 description 3
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000010353 genetic engineering Methods 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000003292 kidney cell Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- 101800005309 Carboxy-terminal peptide Proteins 0.000 description 2
- 101150074155 DHFR gene Proteins 0.000 description 2
- 108010014172 Factor V Proteins 0.000 description 2
- 108010074864 Factor XI Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 229930003448 Vitamin K Natural products 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000005844 autocatalytic reaction Methods 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 229960000182 blood factors Drugs 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000011210 chromatographic step Methods 0.000 description 2
- 238000012411 cloning technique Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000006624 extrinsic pathway Effects 0.000 description 2
- 108010050344 factor X beta Proteins 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229940029329 intrinsic factor Drugs 0.000 description 2
- 230000006623 intrinsic pathway Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 235000019168 vitamin K Nutrition 0.000 description 2
- 239000011712 vitamin K Substances 0.000 description 2
- 150000003721 vitamin K derivatives Chemical class 0.000 description 2
- 229940046010 vitamin k Drugs 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 101800001415 Bri23 peptide Proteins 0.000 description 1
- 101800000655 C-terminal peptide Proteins 0.000 description 1
- 102400000107 C-terminal peptide Human genes 0.000 description 1
- 102100029117 Coagulation factor X Human genes 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000271032 Daboia russelii Species 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108010079356 FIIa Proteins 0.000 description 1
- 206010016077 Factor IX deficiency Diseases 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 108010074105 Factor Va Proteins 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- 201000007176 Factor XII Deficiency Diseases 0.000 description 1
- 201000007371 Factor XIII Deficiency Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 102100023374 Forkhead box protein M1 Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 101000756632 Homo sapiens Actin, cytoplasmic 1 Proteins 0.000 description 1
- 101000907578 Homo sapiens Forkhead box protein M1 Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical group C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- 108010086093 Mung Bean Nuclease Proteins 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 102000002085 Prothrombin/thrombin Human genes 0.000 description 1
- 108050009405 Prothrombin/thrombin Proteins 0.000 description 1
- 101710130181 Protochlorophyllide reductase A, chloroplastic Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 108091005605 Vitamin K-dependent proteins Proteins 0.000 description 1
- 230000003024 amidolytic effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000007219 factor XI deficiency Diseases 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 208000009429 hemophilia B Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- SBUYBNIDQXQZSZ-UHFFFAOYSA-N p-aminophenylphosphocholine Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC1=CC=C(N)C=C1 SBUYBNIDQXQZSZ-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 229940024790 prothrombin complex concentrate Drugs 0.000 description 1
- 108010012557 prothrombin complex concentrates Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 239000002821 viper venom Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6432—Coagulation factor Xa (3.4.21.6)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21006—Coagulation factor Xa (3.4.21.6)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
- a) R1=Val, R2=Thr, R3=Phe, R4=Asp, R5=Asn and optionally R6=Phe (
FIG. 2A , Panel A) (SEQ ID NO:29 and 30), and processed by Factor XIa; - b) R1=Ser, R2=Thr, R3=Leu, R4=Asn (
FIG. 2A , Panel B) (SEQ ID NO:31), and processed by Factor IIa; - c) R1=Ile, R2=Pro, R3=Lys, R4=Ile, and optionally R5=Lys and/or R6=Thr (
FIG. 2A , Panel C) (SEQ ID NOS:32–35), or - R1=Ile, R2=Thr, R3=Ser, R4=Thr, and optionally R5=Lys and/or R6=Thr (
FIG. 2B , Panel I) (SEQ ID NOS:36–39), and processed by Factor XIIa; - d) R1=Ile, R2=Thr, R3=Met, R4=Ser, and optionally R5=Ser and/or R6=Leu (
FIG. 2A , Panel D) (SEQ ID NOS:40–43), and processed by kallikrein; - e) R1=Ile, R2=Gly, R3=Gln, R4=Pro, and optionally R5=Lys and/or R6=Ser (
FIG. 2B , Panel H) (SEQ ID NOS:44–47), or - R1=Ile, R2=Thr, R3=Lys, and R4=Met (
FIG. 2B , Panel E) (SEQ ID NO:48), or - R1=Ile, R2=Gly, R3=Glu, and R4=Ile (
FIG. 2B , Panel F) (SEQ ID NO:49), and processed by Factor Xa; - f) R1=Ile, R2=Lys, R3=Arg, R4=Arg, and optionally R5=Glu and/or R6=Leu (SEQ ID NOS:50–53), or
- R1=Ile, R2=Thr, R3=Val, R4=Arg, and optionally R5=Ala and/or R6=Leu (SEQ ID NOS:54–57), or
- R1=Ile, R2=Arg, R3=Val, R4=Arg, and optionally R5=Gln and/or R6=Leu (SEQ ID NOS:58–61), or
- R1=Ile, R2=Arg, R3=Arg, R4=Arg, and optionally R5=His and/or R6=Leu (SEQ ID NOS:62–65),or
- R1=Ile, R2=Lys, R3=Pro, R4=Arg, and optionally R5=Asn and/or R6=Leu (SEQ ID NOS:66 and 67), or
- R1=Ile, R2=Lys, R3=Arg, R4=Ile, and optionally R5=Arg and/or R6=Leu (SEQ ID NOS:68–71), or
- R1=Ile, R2=Lys, R3=Ser, and R4=Arg (SEQ ID NO:72), or
- R1=Ile, R2=Thr, R3=Val, and R4=Arg (SEQ ID NO:73), or
- R1=Ile, R2=Lys, R3=Leu, and R4=Arg (SEQ ID NO:74) (all see
FIG. 2B , Panel G), with those mentioned under f) being processed by a dibasic endoprotease, such as furin, PACE, kexin/Kex2, furin/PACE, PC1/PC3, PC2, PC4,PACE 4, LPC/PC7, or by a derivative of one of these proteases.
TABLE 1 | |||||
amount of | functional | ||||
incubation | activity | antigen | portion of | ||
(days) | (mU) | (μg/ml) | rFX (%) | ||
CHO − |
0 | 814 | 14 | 58 |
|
1 | 847 | 14 | 61 |
2 | 835 | 14 | 60 | |
3 | 790 | 14 | 56 | |
4 | 763 | 14 | 55 | |
CHO − |
0 | 853 | 14 | 61 |
CHO − |
1 | 1018 | 14 | 73 |
2 | 1099 | 14 | 79 | |
3 | 1135 | 14 | 81 | |
4 | 1198 | 14 | 86 | |
CHO + | 0 | |||
CHO − rFurin | ||||
Plasma FX | 585 | |||
500 mU | ||||
TABLE 2 | |||||
amount of | specific | ||||
incubation | activity | antigen | activity | ||
(hours) | (mU/ml) | μg/ml | mU/μg | ||
rFXRRKR/I + |
0 | <25 | 0.7 | 0 |
6 | <25 | 0.7 | 0 | |
24 | <25 | 0.7 | 0 | |
48 | <25 | 0.7 | 0 | |
72 | <25 | 0.7 | 0 | |
rFXRRKR/I + rfurin | 0 | <25 | 0.7 | 0 |
6 | 56 | 0.7 | 80 | |
24 | 101 | 0.7 | 144 | |
48 | 124 | 0.7 | 177 | |
72 | 133 | 0.7 | 190 | |
CHO + rfurin | 0 | <25 | 0 | |
6 | <25 | 0 | ||
24 | <25 | 0 | ||
48 | <25 | 0 | ||
72 | <25 | 0 | ||
RVV activated | 614 | 4 | 153 | |
plasma FX | ||||
Claims (16)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/407,123 US7220569B2 (en) | 1997-02-27 | 2003-04-04 | Nucleic acids encoding factor X analogues having a modified protease cleavage site |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0033597A AT405516B (en) | 1997-02-27 | 1997-02-27 | FACTOR X-ANALOG WITH MODIFIED PROTEASE SPLIT |
ATA335/97 | 1997-02-27 | ||
PCT/AT1998/000045 WO1998038317A1 (en) | 1997-02-27 | 1998-02-27 | Factor x analogues with a modified protease cleavage site |
US09/367,791 US6573071B1 (en) | 1997-02-27 | 1998-02-27 | Factor X analogues with a modified protease cleavage site |
US10/407,123 US7220569B2 (en) | 1997-02-27 | 2003-04-04 | Nucleic acids encoding factor X analogues having a modified protease cleavage site |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AT1998/000045 Division WO1998038317A1 (en) | 1997-02-27 | 1998-02-27 | Factor x analogues with a modified protease cleavage site |
US09367791 Division | 1998-02-27 | ||
US09/367,791 Division US6573071B1 (en) | 1997-02-27 | 1998-02-27 | Factor X analogues with a modified protease cleavage site |
Publications (2)
Publication Number | Publication Date |
---|---|
US20030181381A1 US20030181381A1 (en) | 2003-09-25 |
US7220569B2 true US7220569B2 (en) | 2007-05-22 |
Family
ID=3487868
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/367,791 Expired - Lifetime US6573071B1 (en) | 1997-02-27 | 1998-02-27 | Factor X analogues with a modified protease cleavage site |
US10/407,123 Expired - Lifetime US7220569B2 (en) | 1997-02-27 | 2003-04-04 | Nucleic acids encoding factor X analogues having a modified protease cleavage site |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/367,791 Expired - Lifetime US6573071B1 (en) | 1997-02-27 | 1998-02-27 | Factor X analogues with a modified protease cleavage site |
Country Status (17)
Country | Link |
---|---|
US (2) | US6573071B1 (en) |
EP (1) | EP0966536B1 (en) |
JP (1) | JP4317976B2 (en) |
AR (1) | AR012034A1 (en) |
AT (2) | AT405516B (en) |
AU (1) | AU744428B2 (en) |
BR (1) | BR9807627A (en) |
CA (1) | CA2282707A1 (en) |
CZ (1) | CZ298298B6 (en) |
DE (1) | DE59813518D1 (en) |
ES (1) | ES2263199T3 (en) |
HU (1) | HU225246B1 (en) |
IL (2) | IL131346A0 (en) |
NO (1) | NO327878B1 (en) |
PL (1) | PL190734B1 (en) |
SK (1) | SK286359B6 (en) |
WO (1) | WO1998038317A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090098119A1 (en) * | 2007-09-28 | 2009-04-16 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
US20090175931A1 (en) * | 2005-11-15 | 2009-07-09 | Camire Rodney M | Compositions and methods for modulating hemostasis |
US20090209463A1 (en) * | 2006-04-20 | 2009-08-20 | Kringle Pharma Inc | Hgf Precursor Protein Variant and Active Protein Thereof |
US20100255000A1 (en) * | 2007-09-28 | 2010-10-07 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
US20110015128A1 (en) * | 2009-07-15 | 2011-01-20 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same |
US8455439B2 (en) | 2008-11-14 | 2013-06-04 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same in combination with blood coagulating agents |
WO2014018120A1 (en) | 2012-07-25 | 2014-01-30 | Catalyst Biosciences, Inc. | Modified factor x polypeptides and uses thereof |
RU2585532C2 (en) * | 2014-01-31 | 2016-05-27 | Федеральное государственное учреждение "Федеральный исследовательский центр "Фундаментальные основы биотехнологии" Российской академии наук"(ФИЦ Биотехнологии РАН) | Plasmid for expression of human recombinant blood clotting factor ix, cho cell producing human recombinant blood clotting factor ix and method of producing said factor |
US9371522B2 (en) | 2011-09-30 | 2016-06-21 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
US9757434B2 (en) | 2013-09-24 | 2017-09-12 | Pfizer Inc. | FXa variant compositions |
US10588950B2 (en) | 2013-01-31 | 2020-03-17 | Pfizer Inc. | Compositions and methods for counteracting Factor Xa inhibition |
US10676731B2 (en) | 2014-08-19 | 2020-06-09 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating factor IX function |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT405517B (en) * | 1997-02-27 | 1999-09-27 | Immuno Ag | FACTOR X-DELETION MUTANTS AND ANALOGS OF THEM |
IL129427A0 (en) * | 1999-04-13 | 2000-02-17 | Yeda Res & Dev | Preparation of biologically active molecules |
AT410216B (en) * | 1999-08-10 | 2003-03-25 | Baxter Ag | X-ANALOG FACTOR WITH IMPROVED ACTIVITY |
AU2001249389A1 (en) * | 2000-03-22 | 2001-10-03 | The Children's Hospital Of Philadelphia | Modified blood clotting factors and methods of use |
US7223577B2 (en) * | 2000-11-17 | 2007-05-29 | Allergan, Inc. | Post-translational modifications and Clostridial neurotoxins |
FR2831170B1 (en) * | 2001-10-19 | 2004-03-19 | Inst Nat Sante Rech Med | MODIFIED PROTEINS C DIRECTLY ACTIVABLE WITH THROMBIN |
FR2841904B1 (en) * | 2002-07-03 | 2004-08-20 | Inst Nat Sante Rech Med | THROMBIN CLAVABLE X FACTOR ANALOGS |
WO2004033630A2 (en) * | 2002-10-04 | 2004-04-22 | Schering Aktiengesellschaft | Modified hepsin molecules having a substitute activation sequence and uses thereof |
ES2346072T3 (en) * | 2004-08-17 | 2010-10-08 | Csl Behring Gmbh | DEPENDENT MODIFIED POLYPEPTIDES OF VITAMIN K. |
EP1728798A1 (en) | 2005-06-01 | 2006-12-06 | ZLB Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
US7855279B2 (en) * | 2005-09-27 | 2010-12-21 | Amunix Operating, Inc. | Unstructured recombinant polymers and uses thereof |
US7846445B2 (en) * | 2005-09-27 | 2010-12-07 | Amunix Operating, Inc. | Methods for production of unstructured recombinant polymers and uses thereof |
EP1820508A1 (en) * | 2006-02-21 | 2007-08-22 | CSL Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
US9956272B2 (en) | 2007-05-30 | 2018-05-01 | Bio Products Laboratory Limited | Methods for preparing factor X, activated factor X, inactivated factor X and inactivated factor Xa, and pharmaceutical compositions comprising same |
GB0710321D0 (en) * | 2007-05-30 | 2007-07-11 | Nhs Blood & Transplant | Method |
KR20100058541A (en) * | 2007-08-15 | 2010-06-03 | 아뮤닉스 인코포레이티드 | Compositions and methods for modifying properties of biologically active polypeptides |
US8703717B2 (en) * | 2009-02-03 | 2014-04-22 | Amunix Operating Inc. | Growth hormone polypeptides and methods of making and using same |
CN116925238A (en) | 2009-02-03 | 2023-10-24 | 阿穆尼克斯制药公司 | Extended recombinant polypeptides and compositions comprising the same |
US8680050B2 (en) * | 2009-02-03 | 2014-03-25 | Amunix Operating Inc. | Growth hormone polypeptides fused to extended recombinant polypeptides and methods of making and using same |
US9849188B2 (en) | 2009-06-08 | 2017-12-26 | Amunix Operating Inc. | Growth hormone polypeptides and methods of making and using same |
CA2764108A1 (en) | 2009-06-08 | 2010-12-16 | Amunix Operating Inc. | Glucose-regulating polypeptides and methods of making and using same |
CN102741422B (en) * | 2009-08-24 | 2016-06-08 | 阿穆尼克斯运营公司 | Factor VII composition and preparation and application thereof |
US8557961B2 (en) | 2010-04-02 | 2013-10-15 | Amunix Operating Inc. | Alpha 1-antitrypsin compositions and methods of making and using same |
JP6256882B2 (en) | 2012-02-15 | 2018-01-10 | アムニクス オペレーティング インコーポレイテッド | Factor VIII composition, and method of making and use of the composition |
JP6383666B2 (en) | 2012-02-15 | 2018-08-29 | バイオベラティブ セラピューティクス インコーポレイテッド | Recombinant factor VIII protein |
WO2013130684A1 (en) | 2012-02-27 | 2013-09-06 | Amunix Operating Inc. | Xten-folate conjugate compositions and methods of making same |
GB201211617D0 (en) * | 2012-06-29 | 2012-08-15 | Univ Aberdeen | Production of cyclic peptides |
FR3001729B1 (en) * | 2013-02-04 | 2015-03-06 | Lab Francais Du Fractionnement | FACTOR X MUTANTS |
EP2970933A2 (en) * | 2013-03-12 | 2016-01-20 | Novo Nordisk A/S | Thrombin sensitive coagulation factor x molecules |
US10548953B2 (en) | 2013-08-14 | 2020-02-04 | Bioverativ Therapeutics Inc. | Factor VIII-XTEN fusions and uses thereof |
BR112018002150A2 (en) | 2015-08-03 | 2018-09-18 | Bioverativ Therapeutics Inc | factor ix fusion proteins and methods of manufacturing and using them |
MX2018002226A (en) | 2015-08-28 | 2018-03-23 | Amunix Operating Inc | Chimeric polypeptide assembly and methods of making and using the same. |
KR102613936B1 (en) * | 2020-11-13 | 2023-12-15 | 한국생명공학연구원 | Kexin enzyme with reduced autolysis and production method thereof |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4359049A (en) | 1980-04-02 | 1982-11-16 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Apparatus for applying a tissue adhesive on the basis of human or animal proteins |
US4501731A (en) | 1983-06-27 | 1985-02-26 | Tishkoff Garson H | Treatment of disparate bleeding disorders with factor X zymogen |
US4735616A (en) | 1985-06-20 | 1988-04-05 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Arrangement for applying a tissue adhesive |
WO1994029370A1 (en) | 1993-06-08 | 1994-12-22 | Enzon, Inc. | Factor ix - polymeric conjugates |
EP0651054A1 (en) | 1993-08-02 | 1995-05-03 | IMMUNO Aktiengesellschaft | Virus-inactivated factor Xa preparation |
US5460950A (en) | 1990-11-26 | 1995-10-24 | Genetics Institute, Inc. | Expression of PACE in host cells and methods of use thereof |
EP0714987A2 (en) | 1994-09-26 | 1996-06-05 | IMMUNO Aktiengesellschaft | Method for quantifying genomic DNA |
US5597799A (en) | 1990-09-04 | 1997-01-28 | Cor Therapeutics, Inc. | Recombinant agents affecting thrombosis |
EP0775750A2 (en) | 1995-11-24 | 1997-05-28 | IMMUNO Aktiengesellschaft | Preparation of proteins from pro-proteins by fusion proteins derived from furin or furinanalogs |
US6562598B1 (en) | 1997-02-27 | 2003-05-13 | Baxter Aktiengesellschaft | Factor X deletion mutants and analogues thereof |
-
1997
- 1997-02-27 AT AT0033597A patent/AT405516B/en not_active IP Right Cessation
-
1998
- 1998-02-25 AR ARP980100832A patent/AR012034A1/en not_active Application Discontinuation
- 1998-02-27 HU HU0100652A patent/HU225246B1/en not_active IP Right Cessation
- 1998-02-27 CA CA002282707A patent/CA2282707A1/en not_active Abandoned
- 1998-02-27 JP JP53706298A patent/JP4317976B2/en not_active Expired - Lifetime
- 1998-02-27 SK SK1171-99A patent/SK286359B6/en not_active IP Right Cessation
- 1998-02-27 ES ES98903943T patent/ES2263199T3/en not_active Expired - Lifetime
- 1998-02-27 IL IL13134698A patent/IL131346A0/en active IP Right Grant
- 1998-02-27 CZ CZ0303299A patent/CZ298298B6/en not_active IP Right Cessation
- 1998-02-27 WO PCT/AT1998/000045 patent/WO1998038317A1/en active IP Right Grant
- 1998-02-27 US US09/367,791 patent/US6573071B1/en not_active Expired - Lifetime
- 1998-02-27 EP EP98903943A patent/EP0966536B1/en not_active Expired - Lifetime
- 1998-02-27 AU AU62002/98A patent/AU744428B2/en not_active Ceased
- 1998-02-27 BR BR9807627-2A patent/BR9807627A/en not_active IP Right Cessation
- 1998-02-27 DE DE59813518T patent/DE59813518D1/en not_active Expired - Lifetime
- 1998-02-27 AT AT98903943T patent/ATE324454T1/en active
- 1998-02-27 PL PL98335382A patent/PL190734B1/en not_active IP Right Cessation
-
1999
- 1999-08-10 IL IL131346A patent/IL131346A/en not_active IP Right Cessation
- 1999-08-26 NO NO19994139A patent/NO327878B1/en not_active IP Right Cessation
-
2003
- 2003-04-04 US US10/407,123 patent/US7220569B2/en not_active Expired - Lifetime
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4359049A (en) | 1980-04-02 | 1982-11-16 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Apparatus for applying a tissue adhesive on the basis of human or animal proteins |
US4501731A (en) | 1983-06-27 | 1985-02-26 | Tishkoff Garson H | Treatment of disparate bleeding disorders with factor X zymogen |
US4735616A (en) | 1985-06-20 | 1988-04-05 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Arrangement for applying a tissue adhesive |
US5597799A (en) | 1990-09-04 | 1997-01-28 | Cor Therapeutics, Inc. | Recombinant agents affecting thrombosis |
US5635481A (en) | 1990-09-04 | 1997-06-03 | Cor Therapeutics, Inc. | Recombinant agents affecting thrombosis |
US5460950A (en) | 1990-11-26 | 1995-10-24 | Genetics Institute, Inc. | Expression of PACE in host cells and methods of use thereof |
WO1994029370A1 (en) | 1993-06-08 | 1994-12-22 | Enzon, Inc. | Factor ix - polymeric conjugates |
EP0651054A1 (en) | 1993-08-02 | 1995-05-03 | IMMUNO Aktiengesellschaft | Virus-inactivated factor Xa preparation |
EP0714987A2 (en) | 1994-09-26 | 1996-06-05 | IMMUNO Aktiengesellschaft | Method for quantifying genomic DNA |
US5858658A (en) | 1994-09-26 | 1999-01-12 | Immuno Aktiengesellschaft | Method of quantitating genomic DNA |
EP0775750A2 (en) | 1995-11-24 | 1997-05-28 | IMMUNO Aktiengesellschaft | Preparation of proteins from pro-proteins by fusion proteins derived from furin or furinanalogs |
US6210929B1 (en) | 1995-11-24 | 2001-04-03 | Baxter Aktiengesellschaft | Fusion protein comprising a furin derivative or a derivative of a furin analogue and a heterologous sequence |
US6562598B1 (en) | 1997-02-27 | 2003-05-13 | Baxter Aktiengesellschaft | Factor X deletion mutants and analogues thereof |
Non-Patent Citations (40)
Title |
---|
Anderson, W. French, Human Gene Therapy. (1998) Nature, ol. 392, pp. 25-30. * |
Bajaj, Satya P., et al.; Simultaneous Purification of Bovine Prothrombin and Factor X; The Journal of Biological Chemistry; Nov. 25, 1973; pp. 7729-7741; vol. 248, No. 22. |
Barr, Philip J.; Mammalian Subtilisins: The Long-Sought Dibasic Processing Endoprotease; Cell; Jul. 12, 1991; pp. 1-3; vol. 66. |
Beinfeld et al. Characterization of an Endoprotease from Rat Small Intestinal Mucosal Secretory Granules Which Generates Somatostatin-28 from Prosomatostatin by Cleavage after a Single Arginine Residue. (1989) J. Biol. Chem. vol. 264, No. 8, pp. 4460-4465. * |
Clackson, Tim, et al.; General applications of PCR to gene cloning and manipulation; PCR A Practical Approach; 1991; pp. 187-214; Oxford University Press. |
Eby, C.S., et al; Characterization of the Structure and Function of the Carboxy Terminal Peptide of Human Factor X; Blood; 1992; p 306a; vol. 80, Supp. 1; 1214. |
Elsinger, F.; Laboratory Tests of Activated Prothrombin Complex Preparations; Activated Prothrombin Complex Concentrates Managing Hemophilia with Factor VIII Inhibitor; 1982; pp. 77-87. |
Fair, Daryl S., et al.; Human Hepatoma Cells Secrete Single Chain Factor X, Prothrombin, and Antithrombin III; Blood; Jul. 1984; pp. 194-204; vol. 64, No. 1. |
Fischer et al. "Structural Analysis of Recombinant von Willebrand Factor: Identification of hetero- and homo-dimers", FEBS Lett., 1994, pp. 345-348, vol. 351. |
Fung, Marion R., et al.; Characterization of an almost full-length cDNA coding for human blood coagulation factor X; Proc. Natl. Acad. Sci. USA; Jun. 1985; pp. 3591-3595; vol. 82. |
Giles, Alan R., et al.; A combination of factor Xa and phosphatidylcholine-phosphatidylserine vesicles bypasses factor VIII in vivo; British Journal of Haematology; 1988; pp. 491-497; vol. 69. |
Gordon, Valery M.; et al.; Proteolytic Activation of Bacterial Toxins by Eukaryotic Cells Is Performed by Furin and by Additional Cellular Proteases; Infect. Immunol.; 1995; pp. 82-87; vol. 69. |
Himmelspach, M. et al. "Alteration of the Specificity of fX Activation by Substitution of Amino Acids Constituting its Activation Site", XVII Congress of the International Society on Thrombosis and Haemostasis, 1999. p. 758. |
International Search Report for PCT/AT 98/00045. dated Jun. 3, 1998. |
Jesty, Jolyon, et al.; The Mechanism of Activation of Factor X: Kinetic Control of Alternative Pathways Leading to the Formation of Activated Factor X; The Journal of Biological Chemistry; Sep. 10, 1974; pp. 5614-5622; vol. 249, No. 17. |
Leytus, S. et al. "Characterization of cDNA coding for human factor X." Proc. Natl. Acad. Sci. USA, Jun. 1984, pp. 3699-3702, vol. 81. |
Leytus, Steven P., et al.; Gene for Human Factor X: A Blood Coagulation Factor Whose Gene Organization Is Essentially Identical with That of Factor IX and Protein C; Biochemistry; Sep. 25, 1986; pp. 5098-5102; vol. 25. |
Magklara et al. Characterization of the enzymatic activity of human kallikrein 6: autoactivation, substrate specificity, and regulation by inhbitors. (2003) Biochem. Biophys. Res. Comm. vol. 307, pp. 948-955. * |
Mertens, Koen, et al.; Pathways in the Activation of Human Coagulation Factor X; Biochem. J.; 1980; pp. 647-658; vol. 185. |
Messier, Terri, L.; Cloning and expression in COS-1 cells of a full-length cDNA encoding human coagulation factor X; Gene; 1991; pp. 291-294; vol. 99. |
Moehring, Joan M., et al.; Strains of CHO-K1 Cells Resistant to Pseudomonas Exotoxin A and Cross-Resistant to Diphtherie Toxin and Viruses; Infection and ImmunitySep. 1983; pp. 998-1009; vol. 41, No. 3. |
Morita, Takashi, et al.: Structural and functional characteristics of a proteolytically modified, "Gla domain-less" bovine factor X and Xa (des light chain residues 1-44); General Biochem; 1980, p. 219; vol. 92; 92:71374k. |
Ngo, J. Thomas, et al.; Computational Complexity, Protein Structure Prediction, and the Levinthal Paradox; The Protein Folding Problem and Tertiary Structure Prediction; 1994; Merz and LeGrand, editors, Birkhauser, Boston, Chapter 14, pp. 492-495. |
Ohnishi, Yukano, et al.; A Furin-Defective Cell Line Is Able to Process Correctly the gp 160 of Human Immunodeficiency Virus Type 1; Journal of Virology; Jun. 1994; pp. 4075-4079; vol. 68, No. 6. |
Original and a translation of 1<SUP>st </SUP>Preliminary Notice in Austrian Patent Application No. A 335/97-1, stamped received Sep. 29, 1997 by the Austrian Patent Office. |
Pryzdial, Edward L.G., et al.; Autoproteolysis of Plasmin-mediated Cleavage of Factor Xao Exposes a Plasminogen Binding Site and Inhibits Coagulation; The Journal of Biological Chemistry; Jul. 12, 1996; pp. 16614-16620; vol. 271, No. 28. |
Pryzdial, Edward W.G.; et al.; Kinetics of Blood Coagulation Factor Xao Autoproteolytic Conversion to Factor Xabeta; The Journal of Biological Chemistry; Jul. 12, 1996; pp. 16621-16626; vol. 271, No. 28. |
Rehemtulla, Alnawaz, et al.; Preferred Sequence Requirements for Cleavage of Pro-von Willebrand Factor by Propeptide-Processing Enzymes; Blood; May 11, 1992; pp. 2349-2355, vol. 79, No. 9. |
Romano et al. Latest Developments in Gene Transfer Technology: Achievements, Perspectives, and Controversies over Therapeutic Applications, (2000) Stem Cells vol: 18, pp. 19-39. * |
Rudolph, Amy E.; Expression, Purification, and Characterization of Recombinant Human Factor X; Protein Expression and Purification; 1997; pp. 373-378; vol. 10; Article No. PT970752. |
Seidah et al. Eukaryotic protein processing: endoproteolysis of precursor proteins, (1997) Curr. Opin. Biotechnol. vol. 8, pp. 602-607. * |
Sherrill, G. Bradley, et al.; Inactivation of human blood coagulation factor X by chemical modification of gamma-carboxyglutamic acid residues; Enzymes; 1985; p. 239; vol. 102; 102:2489q. |
Somia and Verma, Gene Therapy: Trials and Tribulations (2000) Nature Reviews, Genetics, vol. 1, pp. 91-99. * |
Teng, Che-Ming, et al.; Production of Factor X and Factor Xa Variants with Thrombin, Acutin and by Autolysis; Thrombosis Research; 1981; pp. 213-220; vol. 22, No. 1/2. |
Urlaub, Gail, et al.; Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity; Proc. Natl. Acad. Sci USA; Jul. 1980; pp. 4216-4220; vol. 77, No. 7. |
Verma and Somia, Gene therapy-promises, problems, and prospects (1997) Nature vol. 389, pp. 239-242. * |
Wallin, Reidar, et al.; Intracellular Proteolytic Processing of the Two-Chain Vitamin K-Dependent Coagulation FActor X; Thrombosis Research; 1994; pp. 395-403; vol. 73; No. 6. |
Watzke, Herbert H., et al.; Factor X; Molecular Basis of Trhombosis and Hemostatsis; eds. Hight and Roberts; 1995; chapter 11, pp. 239-255. |
Wells, James A.; Additivity of Mulaticnal Effects in Proteins; Biochemistry; Sep. 18, 1990; pp. 8509-8516; vol. 29, No. 3;7. |
Wolf, David L., et al.; Design of Constructs for the Expression of Biologically Active Recombinant Human Factors X and Xa; The Journal of Biological Chemistry; Jul. 25, 1991; pp. 13726-13730; vol. 266, No. 21. |
Cited By (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090175931A1 (en) * | 2005-11-15 | 2009-07-09 | Camire Rodney M | Compositions and methods for modulating hemostasis |
US9896676B2 (en) | 2005-11-15 | 2018-02-20 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
US9410137B2 (en) | 2005-11-15 | 2016-08-09 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
US8383386B2 (en) | 2005-11-15 | 2013-02-26 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
US8278270B2 (en) | 2006-04-20 | 2012-10-02 | Kringle Pharma Inc. | HGF precursor protein variant and active protein thereof |
US20090209463A1 (en) * | 2006-04-20 | 2009-08-20 | Kringle Pharma Inc | Hgf Precursor Protein Variant and Active Protein Thereof |
US8003607B2 (en) * | 2006-04-20 | 2011-08-23 | Kringle Pharma Inc. | HGF precursor protein variant and active protein thereof |
US10954503B2 (en) | 2007-09-28 | 2021-03-23 | Alexion Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US10675335B2 (en) | 2007-09-28 | 2020-06-09 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US8153590B2 (en) | 2007-09-28 | 2012-04-10 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US20100255000A1 (en) * | 2007-09-28 | 2010-10-07 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
US8455441B2 (en) | 2007-09-28 | 2013-06-04 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US10190111B2 (en) | 2007-09-28 | 2019-01-29 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US11839646B2 (en) | 2007-09-28 | 2023-12-12 | Alexion Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US8889129B2 (en) | 2007-09-28 | 2014-11-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US9587233B2 (en) | 2007-09-28 | 2017-03-07 | Portola Pharmaceuticals, Inc. | Antidotes for factor XA inhibitors and methods of using the same |
US9062298B2 (en) | 2007-09-28 | 2015-06-23 | Portola Pharmaceuticals, Inc. | Antidotes for factor XA inhibitors and methods of using the same |
US9109046B2 (en) | 2007-09-28 | 2015-08-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US20090098119A1 (en) * | 2007-09-28 | 2009-04-16 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
US9388401B2 (en) | 2007-09-28 | 2016-07-12 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US8268783B2 (en) | 2007-09-28 | 2012-09-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
US8455439B2 (en) | 2008-11-14 | 2013-06-04 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same in combination with blood coagulating agents |
WO2010117729A1 (en) | 2009-03-30 | 2010-10-14 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
EP3604510A1 (en) | 2009-03-30 | 2020-02-05 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
US10765726B2 (en) | 2009-07-15 | 2020-09-08 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor Xa inhibitors and methods of using the same |
US9056106B2 (en) | 2009-07-15 | 2015-06-16 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor Xa inhibitors and methods of using the same |
US20110015128A1 (en) * | 2009-07-15 | 2011-01-20 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same |
US10106786B2 (en) | 2011-09-30 | 2018-10-23 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
US9371522B2 (en) | 2011-09-30 | 2016-06-21 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
US9856467B2 (en) | 2012-07-25 | 2018-01-02 | Catalyst Biosciences, Inc. | Modified factor X polypeptides and uses thereof |
US9145552B2 (en) | 2012-07-25 | 2015-09-29 | Catalyst Biosciences, Inc. | Modified factor X polypeptides and uses thereof |
WO2014018120A1 (en) | 2012-07-25 | 2014-01-30 | Catalyst Biosciences, Inc. | Modified factor x polypeptides and uses thereof |
US10588950B2 (en) | 2013-01-31 | 2020-03-17 | Pfizer Inc. | Compositions and methods for counteracting Factor Xa inhibition |
US9757434B2 (en) | 2013-09-24 | 2017-09-12 | Pfizer Inc. | FXa variant compositions |
US10660946B2 (en) | 2013-09-24 | 2020-05-26 | Pfizer Inc. | Methods for purifying FXa variant proteins |
RU2585532C2 (en) * | 2014-01-31 | 2016-05-27 | Федеральное государственное учреждение "Федеральный исследовательский центр "Фундаментальные основы биотехнологии" Российской академии наук"(ФИЦ Биотехнологии РАН) | Plasmid for expression of human recombinant blood clotting factor ix, cho cell producing human recombinant blood clotting factor ix and method of producing said factor |
US10676731B2 (en) | 2014-08-19 | 2020-06-09 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating factor IX function |
Also Published As
Publication number | Publication date |
---|---|
DE59813518D1 (en) | 2006-06-01 |
SK286359B6 (en) | 2008-08-05 |
CZ303299A3 (en) | 2000-02-16 |
ES2263199T3 (en) | 2006-12-01 |
IL131346A (en) | 2007-05-15 |
US20030181381A1 (en) | 2003-09-25 |
PL190734B1 (en) | 2005-12-30 |
NO994139D0 (en) | 1999-08-26 |
PL335382A1 (en) | 2000-04-25 |
HUP0100652A1 (en) | 2001-06-28 |
CZ298298B6 (en) | 2007-08-22 |
EP0966536B1 (en) | 2006-04-26 |
JP2001513631A (en) | 2001-09-04 |
AT405516B (en) | 1999-09-27 |
WO1998038317A1 (en) | 1998-09-03 |
SK117199A3 (en) | 2000-05-16 |
CA2282707A1 (en) | 1998-09-03 |
AU6200298A (en) | 1998-09-18 |
IL131346A0 (en) | 2001-01-28 |
JP4317976B2 (en) | 2009-08-19 |
BR9807627A (en) | 2000-02-22 |
US6573071B1 (en) | 2003-06-03 |
HU225246B1 (en) | 2006-08-28 |
AR012034A1 (en) | 2000-09-27 |
ATA33597A (en) | 1999-01-15 |
AU744428B2 (en) | 2002-02-21 |
HUP0100652A3 (en) | 2003-01-28 |
NO994139L (en) | 1999-10-27 |
ATE324454T1 (en) | 2006-05-15 |
NO327878B1 (en) | 2009-10-12 |
EP0966536A1 (en) | 1999-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7220569B2 (en) | Nucleic acids encoding factor X analogues having a modified protease cleavage site | |
US6905846B2 (en) | Nucleic acids encoding factor X deletion mutants and analogues thereof | |
US5753224A (en) | Hybrid protein C | |
EP1238065B1 (en) | Factor x analog with an improved ability to be actived | |
EP0506821B1 (en) | Hybrid protein c | |
MXPA99007768A (en) | Factor x analogues with a modified protease cleavage site | |
MXPA99007817A (en) | Factor x deletion mutants and analogues thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
FPAY | Fee payment |
Year of fee payment: 8 |
|
AS | Assignment |
Owner name: BAXTER INNOVATIONS GMBH, AUSTRIA Free format text: CHANGE OF NAME;ASSIGNOR:BAXTER AKTIENGESELLSCHAFT;REEL/FRAME:036286/0860 Effective date: 19990701 |
|
AS | Assignment |
Owner name: BAXALTA INCORPORATED, ILLINOIS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BAXTER INNOVATIONS GMBH;REEL/FRAME:036366/0301 Effective date: 20150811 Owner name: BAXALTA GMBH, SWITZERLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BAXTER INNOVATIONS GMBH;REEL/FRAME:036366/0301 Effective date: 20150811 |
|
AS | Assignment |
Owner name: BAXTER INNOVATIONS GMBH, AUSTRIA Free format text: CHANGE OF NAME;ASSIGNOR:BAXTER TRADING GMBH;REEL/FRAME:037660/0466 Effective date: 20080109 Owner name: BAXALTA INNOVATIONS GMBH, AUSTRIA Free format text: CHANGE OF NAME;ASSIGNOR:BAXTER INNOVATIONS GMBH;REEL/FRAME:037660/0478 Effective date: 20150501 Owner name: BAXTER EASTERN EUROPE VERTRIEBS GMBH, AUSTRIA Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE EXECUTION DATE AND NAME OF ASSIGNEE PREVIOUSLY RECORDED ON REEL 036286 FRAME 0860. ASSIGNOR(S) HEREBY CONFIRMS THE CHANGE OF NAME;ASSIGNOR:BAXTER AKTIENGESELLSCHAFT;REEL/FRAME:037660/0432 Effective date: 20001116 Owner name: BAXTER TRADING GMBH, AUSTRIA Free format text: CHANGE OF NAME;ASSIGNOR:BAXTER EASTERN EUROPE VERTRIEBS GMBH;REEL/FRAME:037660/0472 Effective date: 20001228 |
|
AS | Assignment |
Owner name: BAXALTA INCORPORATED, ILLINOIS Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR NAME, EXECUTION DATE, AND ADDRESS OF ASSIGNEE BAXALTA GMBH PREVIOUSLY RECORDED ON REEL 036366 FRAME 0301. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNOR:BAXALTA INNOVATIONS GMBH;REEL/FRAME:038324/0691 Effective date: 20160314 Owner name: BAXALTA GMBH, SWITZERLAND Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR NAME, EXECUTION DATE, AND ADDRESS OF ASSIGNEE BAXALTA GMBH PREVIOUSLY RECORDED ON REEL 036366 FRAME 0301. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNOR:BAXALTA INNOVATIONS GMBH;REEL/FRAME:038324/0691 Effective date: 20160314 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 12 |